Hematopoietic stem cells (HSCs) are self-renewing multipotent progenitors that give rise to all blood and immune system cells. The ability of HSCs to persist throughout life is necessary for the constant regeneration of blood cells. The remarkable self-renewal capacity of adult HSCs, is genetically regulated, and dependent upon mechanisms that repress senescence pathways. Mutations that disrupt the ability of adult HSCs to avoid senescence lead to depletion of the HSC pool, hematopoietic failure, and death. Although HSCs persist throughout life, they undergo age-related changes in proliferation, self-renewal potential, and developmental potential. Importantly, age-related changes in the proliferation of HSCs from different mouse strains correlate with strain lifespan, suggesting that age-related changes in HSCs are regulated by mechanisms that are of general importance in aging. Aging is associated with an increased incidence of cancer and degenerative disease, as well as a decreased capacity for repair in several different tissues including the hematopoietic system. Although stem cells are known to play a central role in regeneration and susceptibility to cancer, little attention has been paid to whether there is a link between age-related morbidity and age-related changes in stem cell function. This proposal will test the extent to which age-related changes in HSC function are determined by age-related changes in the expression of specific genes within HSCs. To begin to determine whether changes in stem cell function are linked to age related morbidity, we will also test whether the increased incidence of leukemia and lymphoma in old mice is associated with neoplastic cells within the HSC population. Finally, we will test whether age-related changes in HSC properties are reversible or irreversible in response to changes in the age of the stem cell's environment. Answers to these questions would have fundamental implications for understanding the regulation of stem cell aging, and for generating new strategies for treating age-related morbidity. [unreadable] [unreadable]